The broad, long-term objective of this research is to advance our understanding of the mechanisms that govern cell proliferation and differentiation. This proposal will determine whether the CCAAT/enhancer binding proteins (C/EBPs) regulated development of the myelomonocytic lineage in vitro and in vivo. Expression of the C/EBPs is highly regulated during hematopoiesis. We have made the novel observation that high expression of C/EBPalpha in mouse fibroblastic cells induced the macrophage colony stimulating factor (M-CSF) receptor (c-fms). The M-CSF receptor is a differentiation-specific marker of mononuclear phagocytic lineage and mediates the action of M-CSF, the growth factor which promotes the proliferation/maturation/survival of mononuclear phagocytic cells. Based on these observations and others, we hypothesize that the C/EBPs regulate development of the myelomonocytic lineage. To test this hypothesis, the C/EBPalpha and C/EBPbeta genes will be transduced into hematopoietic stem cells by use of retroviruses and we will determine whether their forced expression increases the production of myelomonocytic cells in vitro and in vivo. A dominant negative mutant of the C/EBPs will be examined for its ability to suppress development of the myelomonocytic linage. The knowledge gained from this research will advance our understanding of developmental control mechanisms and cancer.